Anorectic agent; 4-(3-trifluoromethylphenyl)-1-(2-cyanoethyl)-1,2,3,6-tetrahydropyridine

ABSTRACT

The invention relates to 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridines of formula ##STR1## in which R represents a cyano, acetyl or cycloalkyl group of from 3 to 7 carbon atoms and Alk represents a straight or branched alkylene of from 1 to 4 carbon atoms, as well as to the salts thereof, having an anorectic acitivity, to a process for preparing same and to pharmaceutical compositions containing said compounds, useful in the treatment of obesity.

This is a division of application Ser. No. 630,969, filed July 16, 1984,now U.S. Pat. No. 4,602,024 which Application is a division ofapplication Ser. No. 354,522 filed on Mar. 3, 1982, now U.S. Pat. No.4,472,408.

The present invention relates to novel compounds having anorecticactivity.

More particularly, the invention relates to novel4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridines of formula##STR2## in which R represents a cyano, acetyl or cycloalkyl group offrom 3 to 7 carbon atoms and Alk represents a straight or branchedalkylene group of from 1 to 4 carbon atoms, as well as to theirpharmaceutically acceptable salts, having a noteworthy anorecticactivity.

British Pat. No. GB-A-881 894 describes a series of1-aroylalkyl-4-aryl-1,2,3,6-tetrahydropyridines of general formula##STR3## and pharmaceutically useful non-toxic salts thereof, where Arand Ar' are each a halophenyl radical, alkoxyphenyl radical of less than11 carbon atoms, or a dimethoxyphenyl, hydroxyphenyl, thienyl,trifluoromethylphenyl or monocyclic aromatic radical of less than 11carbon atoms and Alk is an alkylene radical containing from 3 to 6carbon atoms.

One of the processes for preparing the compounds II above provides thereaction of an appropriateω-(4-aryl-1,2,3,6-tetrahydropyridine)alkanonitrile with an arylmagnesium halide, the decomposition of the resulting complex and theisolation of the product.

The above Patent therefore suggests the possibility of using certainω-(4-aryl-1,2,3,6-tetrahydropyridine)alkanonitides as intermediates inthe preparation of compounds having anticonvulsant C.N.S. depressant andtranquillizing action. However, it describes no3-trifluoromethylphenyl-1,2,3,6-tetrahydropyridine substituted by acyanoalkyl group.

It is known that the leading compound having anorectic action isamphetamine which exerts its activity by a central biochemical mechanismof action at the level of the dopaminergic and noradrenergic systems.

Amphetamine and its derivatives have important drawbacks as theircentral nervous system stimulating effect as well as the possibility ofhabit-forming and of pharmaco-dependence may constitute a potentialdanger for the patient.

Studies have therefore been dedicated to the search for amphetaminederivatives which present a dissociation between the stimulant effectand the anorectic action. The introduction of a trifluoromethyl group inthe meta position of the phenyl group of ethylamphetamine led to aproduct, hereinafter designated by its International Non-ProprietaryName "fenfluramine", having excellent anorectic activity, which, insteadof being a stimulant, has a certain sedative action.

The advantage of fenfluramine and of its derivatives over amphetamineand its derivatives is due to the different mechanism of action. Infact, anorexia induced by amphatamine seems to be mediated by therelease of cerebral noradrenaline, while the anorectic action of thefenfluramine depends on the release of the endogenous serotonin of thecentral neurons (Ann. C. Sullivan et al. Appetite Regulation and itsModulation by Drugs, Nutrition and Drug Interrelation, 1978, AcademicPress, 21-82) and on the inhibition of the serotonin uptake.

However, it is known that fenfluramine, at doses very close to theanorectic dose, induces a significant reduction in the cerebral rates ofserotonin (Arch. Intern. Pharmacodyn. Ther. 1967, 170, 276) and that alasting depletion of serotonin may be considered as a sign of potentialneurotoxicity (C. D. Morgan et al. Life Sci. Part I, 11, 83; 1972).

It has now been found that the4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridines of formula Ihereinabove and their salts show a noteworthy anorectic activityassociated with a very low toxicity. From the biochemical standpoint,the compounds of formula I hereinabove, as well as their salts, act asagonists of the cerebral serotonin without inducing any depletion ofcerebral serotonin nor stimulation of the central nervous system. Moreparticularly, the compounds of formula I hereinabove show a greataffinity for the post-synaptic receptors of the serotonin and, by thisdirect stimulation of the serotoninergic system, they show anorecticactivity without the side effects due to the release of serotonin.

Thus the present invention relates to novel4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridines of formula Ihereinabove, as well as to their pharmaceutically acceptable salts.

Pharmaceutically acceptable salts include the nontoxic salts derivedfrom mineral or organic acids such as hydrochloride, hydrobromide,succinate, tartrate, citrate, furmarate, maleate,4,4'-methylenebis-(3-hydroxy-2-naphthoate), hereinafter designated"pamoate", 2-naphthalenesulfonate, hereinafter designated "napsylate",methanesulfonate, hereinafter designated "mesylate", p-toluenesulfonate,hereinafter designated "tosylate", and the like.

According to another of its features, the present invention relates to aprocess for preparing the4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridines of formula Ihereinabove and the salts thereof.

Said process is characterised in that the4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine of formula:##STR4## is reacted, in an organic solvent and at a temperature of 20°to 200° C., with a compound of formula X--R, where R has the meaninggiven hereinabove and X represents a chloro-, bromo- or iodoalkyl groupof from 1 to 4 carbon atoms or, only when R is cyano or acetyl, a vinylgroup which is nonsubstituted or substituted by 1 or 2 methyl groups orby an ethyl group.

The 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine used asstarting material is described in French Pat. Nos. 1 421 208 and 1 459013.

The preferred organic solvent used is an aliphatic alcohol of from 1 to6 carbon atoms, such as methanol, ethanol, n-butanol, n-pentanol, butother solvents such as hexane, dimethylformamide, dimethylsulfoxide,sulfolane, acetonitrile, pyridine and the like may be used.

The reaction is advantageously carried out in the presence of a basiccondensation agent such as triethylamine, especially when R--X is ahalogen derivative.

The reaction temperature may vary between room temperature (about 20°C.) and 200° C. and its duration varies accordingly. After 4 to 5 hoursof heating at 100°-150° C., the reaction is generally complete and theend product thus obtained may be isolated according to conventionaltechniques and optionally converted into its salts by treatment with asolution of the chosen acid in an organic solvent.

According to another aspect, the present invention relates to a processfor preparing the compounds of formula I hereinabove in which Alk isstraight-chained and R is other than cyano and acetyl, namely compoundsof formula: ##STR5## where R' represents a cycloalkyl group containing 3to 7 carbon atoms and n is 1, 2, 3 or 4, characterized in that acompound of formula ##STR6## in which R' and n are such as definedhereinabove, is reduced by an aluminum hydride or by a complex hydrideof aluminum and lithium in an inert organic solvent at a temperature offrom 0° C. to the boiling temperature of the solvent employed and theproduct thus obtained is optionally converted into its pharmaceuticallyacceptable salts.

The reduction is carried out according to modi operandi known per se,using aluminum hydride or a complex hydride of lithium and aluminum,such as LiAlh₄, LiAlH(OCH₃)₃ and the like as reduction agent. Operationis generally carried out in an inert solvent such as an ether, such asdiethyl ether, tetrahydrofuran, dioxan or 1,2-dimethoxyethane.

According to a preferred modus operandi, operation is carried out withan equimolecular amount of lithium and aluminum hydride LiAlH₄ withrespect to the starting compound V, at a temperature of 20°-30° C. indiethyl ether and in an inert atmosphere. After about one hour, thereduction is complete and the compound of formula IV is isolatedaccording to conventional techniques in the form of free base or of oneof its salts.

The free base thus obtained may be converted into one of its salts bysimple salification in an organic solvent such as an alcohol, preferablyethanol and isopropanol, an ether such as 1,2-dimethoxyethane, ethylacetate or a hydrocarbon such as hexane.

The compounds of formula V hereinabove are prepared by reacting the4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine of formula IIIwith a functional derivative of a carboxylic acid of formula:

    R'--(CH.sub.2).sub.n-1 --COOH                              (VI)

where R' and n are such as defined hereinabove, in an organic solvent ata temperature of between -10° C. and the boiling temperature of thesolvent employed.

The suitable derivative used may be anhydride, a mixed anhydride, anactivated ester or an acid halide preferably chloride. Among theactivated esters, the nitrophenyl ester is particularly preferred, butthe methoxyphenyl, trityl, benzhydryl esters and the like are alsosuitable.

The temperature of reaction may vary between 0° C. and the boiling pointof the solvent employed, but operation is generally carried out at roomtemperature or at 30°-50° C. It may be preferable to carry out thereaction in a cold medium when it is exothermic, as when the chloride isused as functional derivative of the benzoic acid of formula VI.

The reaction solvent used is preferably an alcohol such as methanol orethanol, or a halogenated solvent, such as methylene chloride,dichloroethane, chloroform and the like, but other organic solventscompatible with the reagents used, for example dioxan, tetrahydrofuranor a hydrocarbon such as hexane may also be used.

The reaction may be carried out in the presence of a proton acceptor,for example an alkaline carbonate or a tertiary amine, when hydrochloricacid or another acid is formed during the reaction, but this protonacceptor is not essential for obtaining the final product.

The product which is obtained at the end of the reaction is generally anoil which may be isolated and characterized according to conventionaltechniques, but which may be used in the crude state for reduction withthe hydride.

The 4-(3-trifluormethylhenyl)-1,2,3,6-tetrahydropyridines of the presentinvention and their salts show a remarkable, selective anorecticactivity without giving any amphetamine-like effect. The selectivity oftheir action is demonstrated by the lack of secondary pharmacologicalactivities, such as sedative or excitant activity and the actioninhibiting the locomotor activity.

The anorectic activity was assessed by the method of the food intake inthe rat. Female rats weighing 200 g are used, which were trained for 10days to eat during a period of 4 hours, and selected on the eighth day.At the end of the tenth day, the randomized animals were divided into a"control group" treated by the vehicle alone, and into several "treatedgroups". Treatment was effected by the intraperitoneal or oral route 30minutes or 1 hour before presentation of the food and the quantity offood taken during the first hour was then measured.

Table I hereinbelow shows, for seven representative compounds of theinvention:

the acute toxicity, expressed as LD₅₀ in the rat by the oral orintraperitoneal route (A);

the anorectic activity, expressed as oral or intraperitoneal doseinhibiting by 50% the food intake (ID₅₀, B);

the ratio between the acute toxicity and the anorectic activity whichexpresses the therapeutic index related to the acute toxicity (A/B).

The following compounds were used as products representative of thepresent invention:

4-(3-trifluoromethylphenyl)-1-(2-cyanoethyl)-1,2,3,6-tetrahydropyridinehydrochloride (compound of Example 2).

4-(3-trifluoromethylphenyl)-1-(3-cyanopropyl)-1,2,3,6-tetrahydropyridinehydrochloride (compound of Example 3);

4-(3-trifluoromethylphenyl-1-(4-cyanobutyl)-1,2,3,6-tetrahydropyridinehydrochloride (compound of Example 4);

4-(3-trifluoromethylphenyl)-1-acetonyl-1,2,3,6-tetrahydropyridinehydrochloride (compound of Example 5);

4-(3-trifluoromethylphenyl)-1-(3-oxobutyl)-1,2,3,6-tetrahydropyridinehydrochloride (compound of Example 6);

4-(3-trifluoromethylphenyl)-1-cyclopropylmethyl-1,2,3,6-tetrahydropyridinehydrochloride (compound of Example 7);

4-(3-trifluoromethylphenyl)-1-(2-cyclohexylethyl)-1,2,3,6-tetrahydropyridinehydrochloride (compound of Example 10).

                  TABLE I                                                         ______________________________________                                                             A         B                                                        Route of   LD.sub.50 ID.sub.50                                      Compound  administration                                                                           mg/kg     mg/kg A/B                                      ______________________________________                                        Example 2 i.p.       205.8     12.0  17.1                                               oral       254.2     9.5   26.7                                     Example 3 i.p.       258.5     11.1  23.3                                               oral       538.5     11.7  46                                       Example 4 oral       335.6     10.5  32.0                                     Example 5 i.p.       165.0     10.8  15.3                                     Example 6 i.p.       134.2     6.5   20.6                                               oral       298.6     11.8  25.3                                     Example 7 i.p.       135.4     5.5   24.6                                     Example 10                                                                              oral       488.4     2.6   187.8                                    fenfluramine                                                                            i.p.        85.6     5.4   15.8                                               oral       100.4     4.0   25.1                                     ______________________________________                                    

It follows from this Table that the representative compounds of thepresent invention show a good anorectic activity with low toxicity.Their efficacy is comparable, from the standpoint of the therapeuticindex, to that of the reference compound.

From the biochemical standpoint, the4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridines of the presentinvention and their salts differ from the fenfluramine and itsderivatives in their mechanism of action. In fact, the compounds of thepresent invention are post-synaptic agonists of the serotonin with veryweak effects on the pre-synaptic mechanisms, such as the uptake andrelease of the serotonin, on which, on the contrary, fenfluramine acts.The mechanism of action of the compounds of the present inventioninvolves a remarkable anorectic activity and reduced side effects.

In particular, the compounds of the present invention, in vivo, do notinduce any depletion of serotonin at central level. There is thereforeless possibility of the lasting use of the compounds of the presentinvention inducing side effects at central level.

Table II hereinbelow summarizes the cerebral rates of serotonin, inpercentage with respect to the controls, after intraperitoneal or oraladministration of four representative compounds of the presentinvention. The determination of the cerebral rates, according to Curzonand Green (Brit. J. Pharmacol. 39, 653, 1970) was effected one hourand/or two hours after administration. Fenfluramine was used asreference material.

                  TABLE II                                                        ______________________________________                                                                cerebral rates of serotonin                                  Route of Dose    % with respect to controls                            Compound administration                                                                           mg/kg   1 hr.    2 hrs.                                   ______________________________________                                        Example 2                                                                              i.p.       7.5     --       128                                                          15.0    131.0    146                                                          30.0    --       146                                      Example 6                                                                              i.p.       3.25    --       109                                                          7.5     --       108                                                          15.0    --       116                                      Example 7                                                                              i.p.       3.25    --       111                                                          7.5     --       123                                                          15.0    --       119                                      Example 10                                                                             oral       1.25    --       99                                                           2.5     --       95                                                           5       --       101                                      fenfluramine                                                                           i.p.       5       82.9+    --                                                           7.5     81.6+    53.1++                                                       10      79.0++   --                                       ______________________________________                                         + significant P < 0.05                                                        ++ significant P < 0.01                                                  

This Table shows that the products of the present invention, at a dosegreater than the anorectic ED₅₀, do not reduce the cerebral rates ofserotonin, while fenfluramine induces a significant reduction ofcerebral serotonin.

The affinity of the compounds of the present invention for thepost-synaptic serotonin receptors was determined according to the methodof Peroutka and Synder (Molec. Pharmacol. 1979, 16, 687-699) whichconsists in incubating rat cortex membranes with a fixed concentrationof ³ H-serotonin in the presence of different concentrations of product.Table III hereinbelow shows the molar concentration of fiverepresentative compounds of the present invention which give a 50%inhibition of the binding specific to the serotoninergic receptor (IC₅₀)namely the measurement of the product ability to interact with the ³H-serotonin in the binding at its receptor. Fenfluramine was used asreference compound.

                  TABLE III                                                       ______________________________________                                                    .sup.3 H--serotonin binding (2 μM)                             Compound    IC.sub.50 /M/                                                     ______________________________________                                        Example 2   4.3 × 10.sup.-7                                             Example 3   3.1 × 10.sup.-7                                             Example 6   1.1 × 10.sup.-7                                             Example 7   4.1 × 10.sup.-7                                             Example 10  1.8 × 10.sup.-7                                             fenfluramine                                                                              >10.sup.-5                                                        ______________________________________                                    

This Table shows that the compounds of the present invention have a verygood affinity for the post-synaptic serotoninergic receptor while theaffinity of the reference compound for the same receptor is much lower.

Thus, according to another of its aspects, the present invention relatesto pharmaceutical compositions containing, as active ingredients,4-(3-trifluormethylphenyl)-1,2,3,6-tetrahydropyridines of formula Ihereinabove, as well as to their pharmaceutically acceptable additionsalts.

In the pharmaceutical compositions of the present invention for oral,sublingual, sub-cutaneous, intramuscular, intravenous, transdermic orrectal administration, the active ingredients of formula I hereinabovemay be administrered in dosage unit forms mixed with conventionalpharmaceutical carriers, to animals and to human beings for thetreatment of obesity. Among the appropriate dosage forms ofadministration there are the forms by the oral route such as tablets,capsules, powders, granules and oral solutions or suspensions and theforms of sublingual and oral administration, as well as the forms ofparenteral administration useful for subcutaneous, intramuscular orintravenous administration.

In order to obtain the desired anorectic effect, the dose of activeingredient may vary between 0.1 and 100 mg per kg of body weight and perday.

Each unitary dose may contain from 1 to 500 mg of active ingredient incombination with a pharmaceutical support. This unitary dose may beadministered 1 to 4 times per day.

When a solid composition is prepared in the form of tablets, the mainactive ingredient is mixed with a pharmaceutical vehicle such asgelatine, starch, lactose, magnesium stearate, talc, arabic gum or thelike. The tablets may be coated with sucrose or other suitable materialsor they may be treated in another way so that they have an extended ordelayed activity and that they continuously release a predeterminedquantity of active ingredient.

A preparation in capsules is obtained by mixing the active ingredientwith a diluent and by pouring the mixture obtained into soft or hardcapsules.

A preparation in the form of syrup or elixir may contain the activeingredient together with an acaloric sweetening agent, methylparaben andpropylparaben as antiseptics, as well as a flavoring agent and anappropriate dye.

Water-dispersible powders or granules may contain the active ingredientmixed with dispersing agents or wetting agents, or suspending agentssuch as polyvinylpyrrolidone and the like, as well as with sweeteningagents or taste correctors.

For rectal application, suppositories are prepared with binding agentsmelting at rectal temperature, for example cocoa butter orpolyethyleneglycols.

For parenteral application, aqueous suspensions, isotonic salinesolutions or sterile and injectable particular solutions are used, whichcontain pharmacologically compatible dispersing agents and/or wettingagents, for example propyleneglycol or butyleneglycol.

The active ingredient may also be formulated in the form ofmicrocapsules, possibly with one or more carriers or additives.

The compositions of the present invention may contain, in addition tothe 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridines of thepresent invention or one of their pharmaceutically acceptable salts,other active ingredients such as for example tranquillizers,antidepressants, lipid-lowering drugs, antidiabetic drugs or other drugswhich may be used in the treatment of obesity.

The following examples illustrate the invention without, however,limiting the scope thereof.

EXAMPLE 1

A mixture of 0.025 mole of4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine, 3.5 ml oftriethylamine and 0.025 mole of chloroacetonitrile in 40 ml of ethanolis heated to reflux for 5 hours. The reaction mixture is cooled,concentrated and the residue is taken up with diethyl ether. Theethereal solution thus obtained is filtered, washed with water and driedover anhydrous sodium sulfate. To the solution thus obtained is added asaturated solution of hydrogen chloride in isopropanol. In this way, the4-(3-trifluoromethylphenyl)-1-cyanomethyl-1,2,3,6-tetrahydropyridinehydrochloride is obtained which, after crystallization in isopropanol,melts at 169°-172° C. Yield 75% of the theoretical.

EXAMPLES 2 TO 13

By operating as described in Example 1 and by reacting the4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine respectively with3-chloropropionitrile, 4-chlorobutyronitrile, 5-chlorovaleronitrile,chloroacetone, 1-chloro-3-butanone, cyclopropylmethyl chloride,cyclohexylmethyl chloride, 2-cyclopentyl-1-chloroethane,2-cyclohexyl-1-chloroethane, 2-cycloheptyl-1-chlorethane,3-cyclohexyl-1-chloropropane and 2-chloropropionitrile, the compounds ofTable IV hereinbelow are obtained.

                                      TABLE VI                                    __________________________________________________________________________    Example                                                                            Compound                                                                 __________________________________________________________________________    2    4-(3-trifluoromethylphenyl)-1-(2-cyanoethyl)-1,2,3,6-tetrahydro-              pyridine hydrochloride which, after crystallization in 95°             ethanol,                                                                      melts at 226-229° C., yield: 50% of the theoretical.              3    4-(3-trifluoromethylphenyl)-1-(3-cyanopropyl)-1,2,3,6-tetrahydro-             pyridine hydrochloride which, after crystallization in isopropyl              alcohol, melts at 168-170° C. Yield: 46.7% of the                      theoretical.                                                             4    4-(3-trifluoromethylphenyl)-1-(4-cyanobutyl)-1,2,3,6-tetrahydro-              pyridine hydrochloride which, after crystallization in isopropanol,           melts at 146-148° C. Yield: 45% of the theoretical.               5    4-(3-trifluoromethylphenyl)-1-acetonyl-1,2,3,6-tetrahydropyridine             hydrochloride which, after crystallization in isopropyl alcohol,              melts at 188-190° C. Yield: 56% of the theoretical.               6    4-(3-trifluoromethylphenyl)-1-(3-oxobutyl)-1,2,3,6-tetrahydropyridine         1                                                                             hydrochloride which, after crystallization in isopropanol, melts              at 173-176° C. Yield: 45% of the theoretical.                     7    4-(3-trifluoromethylphenyl)-1-cyclopropylmethyl-1,2,3,6-tetrahydro-           pyridine hydrochloride which, after crystallization in acetone,               melts at 178-180° C. Yield: 35% of the theoretical.               8    4-(3-trifluoromethylphenyl)-1-cyclohexylmethyl-1,2,3,6-tetrahydro-            pyridine hydrochloride which, after crystallization in a 1:4                  mixture                                                                       of isopropanol-ethyl acetate, melts at 217-220° C. Yield: 45%          of                                                                            the theoretical.                                                         9    4-(3-trifluoromethylphenyl)-1-(2-cyclopentylethyl)-1,2,3,6-tetrahydro         -                                                                             pyridine hydrochloride which, after crystallization in isopropanol,           melts at 240-245° C. Yield: 39% of the theoretical.               10   4-(3-trifluoromethylphenyl)-1-(2-cyclohexylethyl)-1,2,3,6-tetrahydro-         8                                                                             pyridine hydrochloride which, after crystallization in isopropanol,           melts at 252-257° C. Yield: 48% of the theoretical.               11   4-(3-trifluoromethylphenyl)-1-(2-cycloheptylethyl)-1,2,3,6-tetrahydro         -                                                                             pyridine hydrochloride which, after crystallization in isopropanol,           melts at 262-265° C. Yield: 40% of the theoretical.               12   4-(3-trifluoromethylphenyl)-1-(3-cyclohexylpropyl)-1,2,3,6-tetrahydro         -                                                                             pyridine hydrochloride which, after crystallization in acetone,               melts at 219-222° C. Yield: 25% of the theoretical.               13   4-(3-trifluoromethyl)-1-(2-cyano-1-methyl) ethyl-1,2,3,6-tetra-               hydropyridine hydrochloride.                                             __________________________________________________________________________

EXAMPLE 14

A mixture of 0.03 mole of4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine, of 3.8 ml oftriethylamine and 0.03 mole of 3-chloropropionitrile in 40 ml of ethanolis heated to reflux for 4 hours. The reaction mixture is cooled,concentrated, the residue is taken up with diethyl ether and filtered.By treating the ethereal solution thus obtained, containing4-(3-trifluoromethylphenyl)-1-(2-cyanoethyl)-1,2,3,6-tetrahydropyridinein the form of base, with p-toluenesulfonic acid, maleic acid and,2-naphthalenesulfonic acid, respectively, the following are obtained:

the tosylate of4-(3-trifluoromethylphenyl)-1-(2-cyanoethyl)-1,2,3,6-tetrahydropyridinewhich, after crystallization from acetone, melts at 154°-158° C.;

the maleate of4-(3-trifluoromethylphenyl)-1-(2-cyanoethyl)-1,2,3,6-tetrahydropyridinewhich, after crystallization from acetone, melts at 85°-95° C.; and,

the napsylate of4-(3-trifluoromethylphenyl)-1-(2-cyanoethyl)-1,2,3,6-tetrahydropyridinewhich, after crystallization from acetone, melts at 178°-180° C.

Similarly, the following are obtained:

the maleate of4-(3-trifluoromethylphenyl)-1-cyclopropylmethyl-1,2,3,6-tetrahydropyridinewhich, after trituration in diethyl ether, melts at 78°-80° C.;

the napsylate of4-(3-trifluoromethylphenyl)-1-cyclopropylmethyl-1,2,3,6-tetrahydropyridinewhich, after crystallization from a mixture of water-acetone, melts at139° to 142° C.; and,

the tosylate of4-(3-trifluoromethylphenyl)-1-cyanopropylmethyl-1,2,3,6-tetrahydropyridinewhich, after crystallization from acetone, melts at 86°-88° C.

EXAMPLE 15

0.0263 mole of acrylonitrile is added to a solution of 0.025 mole of4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine in 19 ml ofanhydrous ethanol. The reaction mixture is stirred at room temperaturefor 2 hours, then 50 ml of ethanol and, thereafter, a solution ofhydrochloric acid in ethanol are added. The4-(3-trifluoromethylphenyl)-1-(2-cyanoethyl)-1,2,3,6-tetrahydropyridinehydrochloride identical to the product described in Example 2, is thusobtained by precipitation. Yield: 68.9% of the theoretical.

In the same way, by reacting the4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine withvinyl-methylketone, the4-(3-trifluoromethylphenyl)-1-(3-oxobutyl)-1,2,3,6-tetrahydropyridinehydrochloride, identical to the product described in Example 6, isobtained. Yield: 60.2% of the theoretical.

Under the same operating conditions, by reacting the4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine withcrotononitrile, the4-(3-trifluoromethylphenyl)-1-(2-cyano-1-methyl)ethyl-1,2,3,6-tetrahydropyridinehydrochloride is obtained.

EXAMPLE 16

(a) To a solution of 9.1 g of4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine and of 4.04 g oftriethylamine in 40 ml of methylene chloride cooled to 0° C., a solutionof 4.2 g of chloride of cyclopropanecarboxylic acid in 20 ml ofmethylene chloride is added dropwise, while ensuring that thetemperature does not exceed 5° C. The reaction mixture is left for 30minutes at 0°-5° C., then for one hour at room temperature. 200 ml ofdiethyl ether are added, the mixture is filtered, the organic phase iswashed three times with water, dried and evaporated to dryness underreduced pressure. Thus 11.5 g of4-(3-trifluoromethylphenyl)-1-cyclopropylcarbonyl-1,2,3,6-tetrahydropyridineare obtained: yellow/brown oil containing traces of impurities.

In the same way, by reacting the4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine withcyclohexylcarbonyl, cyclohexylacetyl, 3-cyclohexylpropionyl,cyclopentylacetyl and cycloheptylacetyl chloride in the presence oftriethylamine, the following are respectively obtained:

4-(3-trifluoromethylphenyl)-1-cyclohexylcarbonyl-1,2,3,6-tetrahydropyridine,yellowish oil;

4-(3-trifluoromethylphenyl)-1-cyclohexylacetyl-1,2,3,6-tetrahydropyridine,yellowish oil;

4-(3-trifluoromethylphenyl)-1-(3-cyclohexylpropionyl)-1,2,3,6-tetrahydropyridine,yellowish oil;

4-(3-trifluoromethylphenyl)-1-cyclopentylacetyl-1,2,3,6-tetrahydropyridine,crude oil; and

4-(3-trifluoromethylphenyl)-1-cycloheptylacetyl-1,2,3,6-tetrahydropyridine,impure oil.

(b) To a mixture of 1.5 g of LiAlH₄ and 60 ml of diethyl ether at25°-30° C., 11 g of4-(3-trifluoromethylphenyl)-1-cyclopropylcarbonyl-1,2,3,6-tetrahydropyridineand 50 ml of anhydrous diethyl ether are added in 30 minutes. Theproduct is left for 2 hours with stirring at room temperature, thenwater is added, the ethereal phase is separated by decantation, driedover anhydrous sodium sulfate and the solvent is evaporated underreduced pressure. The residue oil, constituted by4-(3-trifluoromethylphenyl)-1-cyclopropylmethyl-1,2,3,6-tetrahydropyridinebase, is dissolved in isopropanol and the solution is acidified withhydrogen chloride. In this way is obtained the4-(3-trifluoromethylphenyl)-1-cyclopropylmethyl-1,2,3,6-tetrahydropyridinehydrochloride which, after crystallization from 50 ml of acetone, meltsat 178°-180° C. Yield: 46.5%.

In the same way, the following are obtained:

4-(3-trifluoromethylphenyl)-1-cyclohexylmethyl-1,2,3,6-tetrahydropyridineand its hydrochloride which melts at 217°-220° C.;

4-(3-trifluoromethylphenyl)-1-(2-cyclohexylethyl)-1,2,3,6-tetrahydropyridineand its hydrochloride which melts at 252°-257° C.;

4-(3-trifluoromethylphenyl)-1-(3-cyclohexylpropyl)-1,2,3,6-tetrahydropyridineand its hydrochloride which melts at 219°-222° C.;

4-(3-trifluoromethylphenyl)-1-(2-cyclopentylethyl)-1,2,3,6-tetrahydropyridineand its hydrochloride which melts at 240°-245° C.; and

4-(3-trifluoromethylphenyl)-1-(2-cycloheptylethyl)-1,2,3,6-tetrahydropyridineand its hydrochloride which melts at 262°-265° C.

EXAMPLE 17

To a mixture of 0.152 mole of LiAlH(OCH₃)₃ and 60 ml of anhydrousdiethyl ether at room temperature 0.038 mole of4-(3-trifluoromethylphenyl)-1-(3-cyclohexylpropionyl)-1,2,3,6-tetrahydropyridineand 50 ml of anhydrous diethyl ether are added in 30 minutes. Theproduct is left for 2 hours with stirring at room temperature, thenwater is added, the ethereal phase is decanted, dried over anhydroussodium sulfate and the solvent is evaporated under reduced pressure. Theoily residue constituted by4-(3-trifluoromethylphenyl)-1-(3-cyclohexylpropyl)-1,2,3,6-tetrahydropyridinebase, is dissolved in isopropanol and the solution thus obtained isacidified with hydrogen chloride. In this way is obtained the4-(3-trifluoromethylphenyl)-1-(3-cyclohexylpropyl)-1,2,3,6-tetrahydropyridinehydrochloride which, after crystallization from acetone, melts at219°-222° C.

EXAMPLE 18

To a mixture of 0.114 mole of AlH₃ and 60 ml anhydrous tetrahydrofuranare added 0.038 mole of4-(3-trifluoromethylphenyl)-1-cycloheptylacetyl-1,2,3,6-tetrahydropyridineand 50 ml tetrahydrofuran. The product is heated to reflux for 2 hourswith stirring, then cooled. Water is added, the ethereal phase isdecanted, dried over anhydrous sodium sulfate and the solvent isevaporated under reduced pressure. The oily residue constituted by the4-(3-trifluoromethylphenyl)-1-(2-cycloheptylethyl)-1,2,3,6-tetrahydropyridinebase, is dissolved in isopropanol and the solution thus obtained isacidified with hydrogen chloride. In this way is obtained the4-(3-trifluoromethylphenyl)-1-(2-cycloheptylethyl)-1,2,3,6-tetrahydropyridinehydrochloride which, after crystallization in isopropanol, melts at262°-265° C.

EXAMPLE 19

Capsules containing the4-(3-trifluoromethylphenyl)-1-(2-cyanoethyl)-1,2,3,6-tetrahydropyridinehydrochloride and having the following composition:

    ______________________________________                                        Active ingredient                                                                              15           mg                                              lactose          120          mg                                              Magnesium stearate                                                                             5            mg                                              ______________________________________                                    

are prepared by intimately mixing the above ingredients and by pouringthe mixture in capsules of hard gelatine.

EXAMPLE 20

Tablets containing the4-(3-trifluoromethylphenyl)-1-(2-cyanoethyl)-1,2,3,6-tetrahydropyridinehydrochloride and having the following composition:

    ______________________________________                                        Active ingredient  20          mg                                             lactose            100         mg                                             microcrystalline cellulose                                                                       30          mg                                             dried cornstarch   40          mg                                             magnesium stearate 5           mg                                             ______________________________________                                    

are prepared by crushing the active ingredient to a particle dimensionof 0.4 mm, passing it through a sieve of 0.4 mm mesh opening, mixing thecrushed mixture with the other constituents and compressing to formtablets.

In the same way, tablets containing 40 mg of active ingredient areprepared.

EXAMPLE 21

By operating as described in Example 20 hereinabove, tablets having thefollowing composition are prepared:

    ______________________________________                                        Active ingredient                                                                              50           mg                                              lactose          95           mg                                              cornstarch       100          mg                                              talc             4.5          mg                                              magnesium stearate                                                                             0.5          mg                                              ______________________________________                                    

EXAMPLE 22

10,000 capsules with a content of active substance of 50 mg are preparedfrom the following constituents: 500 g of4-(3-trifluoromethylphenyl)-1-(3-oxobutyl)-1,2,3,6-tetrahydropyridinehydrochloride, 495 g of microcrystalline cellulose, 5 g of amorphoussilica gel. The above constituents are mixed well and introduced intocapsules of hard gelatine of dimension 4.

EXAMPLE 23

A sterile aqueous solution appropriate for parenteral use, in ampules,is prepared, having the following composition:

    ______________________________________                                        Hydrochloride of    30         mg                                             4-(3-trifluoromethylphenyl)-                                                  1-(2-cyanoethyl)-1,2,3,6-                                                     tetrahydropyridine                                                            sodium chloride     5          mg                                             Distilled water     to 2       ml                                             ______________________________________                                    

EXAMPLE 24

Suppositories are prepared, having the following composition:

    ______________________________________                                        Hydrochloride of    50         mg                                             4-(3-trifluoromethylphenyl)-                                                  1-(2-cyanoethyl)-1,2,3,6-                                                     tetrahydropyridine                                                            lactose             250        mg                                             Witepsol W 45       to 1.7     g                                              ______________________________________                                    

The active substance is mixed with the lactose and the mixture is placeduniformly in suspension in the molten mass for suppositories. Thesuspension is poured into cooled molds to form suppositories weighing1.7 g.

In the same way, suppositories are prepared, containing

50 mg of4-(3-trifluoromethylphenyl)-1-cyanomethyl-1,2,3,6-tetrahydropyridinehydrochloride or 50 mg of4-(3-trifluoromethylphenyl)-1-(3-cyanopropyl)-1,2,3,6-tetrahydropyridinehydrochloride.

EXAMPLE 25

Tablets having the following composition are prepared:

    ______________________________________                                        hydrochloride of     25        mg                                             4-(3-trifluoromethylphenyl)-1-                                                (2-cyano-1-methyl)ethyl-1,2,3,6-                                              tetrahydropyridine                                                            lactose              95        mg                                             corn starch          45        mg                                             colloidal silica     2         mg                                             soluble starch       5         mg                                             magnesium stearate   3         mg                                             ______________________________________                                    

The active substance is mixed with part of the adjuvants and the mixtureis granulated with a solution of soluble starch in water. After dryingthe granulate, the rest of the adjuvants is added and tablets are formedby compression.

In the same way, tablets are prepared, containing:

25 mg of4-(3-trifluoromethylphenyl)-1-cyanomethyl-1,2,3,6-tetrahydropyridinehydrochloride;

25 mg of4-(3-trifluoromethylphenyl)-1-(2-cyanoethyl)-1,2,3,6-tetrahydropyridinehydrochloride;

25 mg of4-(3-trifluoromethylphenyl)-1-(3-cyanopropyl)-1,2,3,6-tetrahydropyridinehydrochloride; and,

25 mg of4-(3-trifluoromethylphenyl)-1-oxobutyl-1,2,3,6-tetrahydropyridinehydrochloride.

EXAMPLE 26

Tablets containing the4-(3-trifluoromethylphenyl)-1-(3-cyanopropyl)-1,2,3,6-tetrahydropyridine,having the following composition:

    ______________________________________                                        active ingredient  20          mg                                             lactose            100         mg                                             microcrystalline cellulose                                                                       30          mg                                             dried corn starch  40          mg                                             magnesium stearate 5           mg                                             ______________________________________                                    

are prepared by using the process described in Example 20.

In the same way, tablets containing 40 mg of active ingredient areprepared.

EXAMPLE 27

20,000 capsules containing 50 mg of active ingredient are prepared fromthe following constituents:

1000 g of4-(3-trifluoromethylphenyl)-1-(3-cyclohexylpropyl)-1,2,3,6-tetrahydropyridinehydrochloride, 990 g of microcrystalline cellulose and 10 g of amorphoussilica gel. The above constituents are mixed well and introduced intocapsules of hard gelatine of dimension 4.

In the same way, capsules are prepared containing 50 mg of4-(3-trifluoromethylphenyl)-1-(2-cyclopentylethyl)-1,2,3,6-tetrahydropyridinehydrochloride and 50 mg of4-(3-trifluoromethylphenyl)-1-(2-cyclohexyl-ethyl)-1,2,3,6-tetrahydropyridinehydrochloride respectively.

We claim: 1.4-(3-trifluoromethylphenyl)-1-(2-cyanoethyl)-1,2,3,6-tetrahydropyridineor a pharmaceutically acceptable acid addition salt thereof.